For 30 years, this Program Project Grant (PPG) has pioneered new surgical, immunologic, histopathologic and molecular approaches to diagnosis and prognosis of patients with melanoma. Sentinel node biopsy (SNB), now standard for melanoma and breast cancer, was developed under this PPG; its accuracy for staging melanoma was confirmed during the current funding period (first Multicenter Selective Lymphadenectomy Trial, MSLT-I); and its therapeutic potential without further nodal dissection will be determined by continued accrual and randomization of subjects for MLST-II (Project Ill). Project III continues the follow-up of subjects in MSLT-I to determine if the long-term follow-up reveals a significant difference in melanoma specific survival, in addition to the documented improvement in disease-free survival. Project I will provide the histopathology quality review for these two phase III trials, and Project II will provide the molecular data required for stratification of patients in MSLT-II (first use of qRT-PCR to guide therapy in an international trial). As part of this PPG's commitment to translational research and multidisciplinary integration, Projects I, II, III, & Core A will collaborate in the development of a comprehensive prognostic index based on characteristics of primary tumor, immune microenvironment of SN, and serum assays of antibody, mRNA and DNA biomarkers. Specimens from MSLT and non-MSLT studies will be used to develop and assess new molecular biomarkers (Projects II and Ill) and to investigate histopathologic markers relating to SN tumor burden, architecture, and microenvironment (Projects I and Ill). These markers enable us to determine the likelihood of metastasis beyond the SN and thereby identify candidates for CLND and adjuvant therapy. Projects I and III also investigate the biology and pathophysiology of the SN, while Projects I, II and III, with the help of Core C (Molecular Diagnostics and Support) will develop molecular and immunologic markers for detection of occult systemic metastases. These studies are designed directly together with Core A (Biostatistics). Core B (Administration and Multicenter Trial Operations Center) is a unique, complex core in charge with the administration of the grant and the operations center of the two major Phase III clinical trials.